Pharmaceutical agents to treat cancer and/or tumors are widely sought. Antiangiogenesis agents are being pursued as a promising antitumor therapeutic agents. Combretastatin A-4 is one such antiangiogenesis agent. Studies have demonstrated that combretastatin A-4 disrupts the microtubules of human umbilical vein endothelial cells (HUVEC) in culture. It has also been shown that the tubulin-binding properties shown in cell-free systems are retained when the compound enters cells, and that tubulin binding is a significant component of biological activity.
The African Bush Willow Combretum caffrum has proved to be a very important source of cancer cell growth inhibitory constituents named combretastatins. The most potent of these constituents is combretastatin A-4 (1a, “CA-4”), and its sodium phosphate derivative (1b, “CA-4P”) was advanced to Phase I human cancer clinical trials in 1998. (Remick, S. C., et al., (1999) Phase I Pharmacokinetics Study of Single Dose Intravenous (IV) Combretastatin A-4 Prodrug (CA4P) in Patients (pts) with Advanced Cancer, Molecular Targets and Cancer Therapeutics Discovery Discovery, Development, and Clinical Validation, Proceedings of the AACR-NCI-EORTC International Congress, Washington, D.C., #16, p. 4.) Overall results continue to be promising, and human cancer Phase II and combination Ib trials are currently underway.
Antivascular, antiangiogenesis and general antimetastatic activities of CA4P as well as its synergistic utility in combination with other anticancer drugs, radioimmunotherapy and hyperthermia are all areas of active research interest. (see Griggs, J., et al., Combretastatin A-4 Disrupts Neovascular Development in Non-Neoplastic Tissue, British J. of Cancer 2001, 84, 832-835; Folkman, J., Angiogenesis-Dependent Diseases, Seminars in Oncology 2001, 28, 536-542; Kruger, E. A. et al., Approaches to Preclinical Screening of Antiangiogenic Agents, Seminars in Oncology 2001, 28, 570-576; Jin, X., et al., Evaluation of Endostatin Antiangiogenesis Gene Therapy in vitro and in vivo, Cancer Gene Therapy 2001, 8, 982-989; Vacca, A., et al., Bone Marrow Angiogenesis in Patients with Active Multiple Myeloma, Seminars in Oncology 2001, 28, 543-550; Rajkumar, S. V., et al., Angiogenesis in Multiple Myeloma, Seminars in Oncology 2001, 28, 560-564, Griggs, J., et al., Potent Anti-metastatic Activity of Combretastatin A-4, Int. J. Oncol. 2001, 821-825; Pedley, R. B. et al., Eradication of Colorectal Xenografts by Combined Radioimmunotherapy and Combretastatin A-4 3—O-Phosphate, Cancer Research 2001, 61, 4716-4722; Eikesdal, H. P., et al., Tumor Vasculature is Targeted by the Combination of Combretastatin A-4 and Hyperthermia, Radiotherapy and Oncology 2001, 61, 313-320.)
Several of the compounds of the present invention are particularly concerned with treatment of thyroid gland cancer. By 2002, some 20,000 people in the United States were diagnosed with carcinoma of the thyroid gland; of these the distribution was about 80% papillary and 14% follicular differentiated carcinomas derived from follicular epithelial cells producing thyroid hormone. Of the remaining thyroid malignancies, about 4% were medullary carcinoma (neuroendocrine) and 2% of the exceptionally aggressive anaplastic carcinoma (median survival 4-5 months and a near 100% lethal outcome). Significantly, the incidence of both follicular and anaplastic carcinomas are elevated in geographic areas of iodine deficiency. Radiation exposure represents the most general risk factor for thyroid cancer. In addition, excess production of the pituitary hormone thyroid-stimulating hormone (THS), which is very important in regulating thyroid gland growth and function, may be important in the etiology of thyroid cancer. Previously used clinical treatments for thyroid cancer include surgery, suppression of THS, 131I-radiotherapy, and anticancer drugs. But in 2002, another 1,300 victims of thyroid cancer in the U.S. died, emphasizing the great need for more routinely effective anticancer drugs.